MacKenzie BreAnne, Henneke Ingrid, Hezel Stefanie, Al Alam Denise, El Agha Elie, Chao Cho-Ming, Quantius Jennifer, Wilhelm Jochen, Jones Matthew, Goth Kerstin, Li Xiaokun, Seeger Werner, Königshoff Melanie, Herold Susanne, Rizvanov Albert A, Günther Andreas, Bellusci Saverio
German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California;
Am J Physiol Lung Cell Mol Physiol. 2015 May 15;308(10):L1014-24. doi: 10.1152/ajplung.00291.2014. Epub 2015 Mar 27.
Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice.
成纤维细胞生长因子（Fgfs）介导器官修复。博来霉素损伤后肺上皮细胞中Fgf10的过表达具有保护和治疗作用，表现为存活率提高和纤维化减轻。外源性给予FGF7（帕利夫明）在小鼠中也显示出预防性的生存益处。内源性Fgfr2b配体在博来霉素诱导的肺纤维化中的作用仍不清楚。本研究报告了博来霉素肺损伤后野生型小鼠内源性Fgfr2b配体、受体和信号靶点的表达。此外，通过使用基于强力霉素（dox）的可诱导、可溶性、显性负性形式的Fgfr2b受体，测试了在博来霉素诱导的纤维化后减弱内源性Fgfr2b配体的影响。双转基因（DTG）Rosa26(rtTA/+);tet(O)solFgfr2b小鼠被验证了可溶性Fgfr2b的表达和活性（上颌切牙再生失败，肺中重组FGF7信号减弱）。如先前报道，在出生后第1天（PN）至PN105暴露的DTG（+dox）小鼠中未检测到肺形态计量学缺陷。雌性单转基因（STG）和DTG小鼠接受不同水平的博来霉素损伤（1.0、2.0和3.0 U/kg）。Fgfr2b配体在整个损伤过程中（第0 - 11天；第0 - 28天）或后期阶段（第6 - 28天和第14 - 28天）被减弱。在DTG小鼠中未检测到存活率、体重、肺功能、纤维化融合面积或羟脯氨酸沉积的显著变化。这些结果表明，内源性Fgfr2b配体不能显著保护小鼠免受博来霉素损伤，也不能加速博来霉素诱导的肺损伤的消退。
